Composition for the prevention and/or treatment of osteoporosis and alterations due to menopause syndrome

ABSTRACT

A composition that may take the form of a dietary supplement or of a medicament is disclosed which comprises as active ingredients propionyl L-carnitine and the isoflavone genistein for the therapeutic treatment of osteoporosis and menopause syndrome.

The present invention relates to a composition for the prevention and/ortreatment of osteoporosis and alterations due to menopause syndrome.

Accordingly the composition may take the form and exert the action of adietary supplement or of an actual medicine, depending upon the supportor preventive action, or the strictly therapeutic action, which thecomposition is intended to exert in relation to the particularindividuals it is to be used in.

Particularly the present invention relates to a composition whichcomprises in combination:

(a) propionyl L-carnitine or a pharmacologically acceptable saltthereof, optionally in combination with at least another “carnitine”where for “carnitine” is intended L-carnitine or an alkanoyl L-carnitineselected from the group comprising acetyl-L-carnitine, valerylL-carnitine, isovaleryl L-carnitine or their pharmacologicallyacceptable salts; and

(b) 4′,5,7-trihydroxyisoflavone (genistein) optionally in combinationwith at least another isoflavone selected from the group comprising4′,7-dihidroxyisoflavone (daidzein), its 7-glucoside (daidzin) and its4,7-diglucoside.

The new composition can be orally, parenterally, rectally ortransdermally administered and results particularly useful both tohumans and animals, as a dietary supplement or as an actual medicine.

As is well known, postmenopausal syndrome is characterised by numerousmanifestations including vascular effects ranging from hot flushes to anincreased risk of cardiovascular accidents, as well as mental and mooddisorders, and the occurrence of osteoporosis.

The risk of tumours also increases in this period.

Osteoporosis is a prevalent disease in elderly subjects, but it isparticularly postmenopausal women who are most affected.

Osteoporosis, cardiovascular accidents and tumour risk are, in fact, themost frequent events in postmenopausal women.

The therapeutic approaches for the prevention and treatment of thepathological abnormalities accompanying this period are multiple andinvolve the use of minerals such as calcium, vitamins such as vitamin D,or calcitonin, but the most wide-spread therapy consists in hormonereplacement treatment (HRT).

Oestrogen treatment, in fact, is clearly indicated in postmenopausaldisorders as replacement therapy for a well documented deficiency ofsuch hormones.

The use of these hormones, however, is by no means risk-free. Well knownare the thromboembolic risks related to the use of oestrogens and theseconstitute one of the factors limiting their use. The most seriousfactor, however, is above all the carcinogenic risk. Oestradiol andprogesterone, as well as dihydrotestosterone receptors have, in fact,been described in primary tumours of the large bowel and breast.Activation of these receptors has been postulated as one of thepathogenetic causes of these tumours.

Hormone replacement therapy (HRT) is associated with a series of sideeffects consisting not only in the thromboembolic and carcinogenic risk,but also in weight gain, headache, nausea, depression, and breastswelling and tension.

Additional manifestations regarded as contraindications are the presenceof endometriosis, uterine fibroids or previous breast and uterinetumours, which often prompt the physician to abandon this type oftherapy and look for other safer solutions.

Isoflavones and phyto-oestrogens would appear to offer a validalternative.

The indication that vegetable derivatives are capable of exerting anoestrogen-like action has emerged from the finding that animals fed onMedicago sativa or Trifolium repens present disorders of thereproductive capability. The cause of this effect has been traced to thepresence in these plants of coumesterol, a substance structurallysimilar to oestradiol and classed among the phyto-oestrogens.

Substances which are naturally occurring in the vegetable world withstructures and functions similar to 17β-oestradiol are regarded asphyto-oestrogens. This category includes numerous compounds such aslignans, isoflavones, coumestans and lactones of resorcylic acid.Phyto-oestrogens are present in many cereals and legumes. Legumes suchas soy are particularly rich in isoflavones, while lignans are presentin almost all cereals and, above all, in linseed oil.

Phyto-oestrogens may derive from precursors present in the diet afterbacterial modification in the stomach or gut.

The main derivatives from bacterial modification of lignans are.enterodiol and enterolactone, whereas the main isoflavone derivativesafter bacterial removal of the glycoside part are genistein, daidzeinand equol.

Most of these phyto-oestrogens have been identified in human plasma andsaliva, as well as in prostate fluid and mammary cyst aspirate.

All phyto-oestrogens possess oestrogen-like activity, though it isinferior to that of oestradiol.

Epidemiological research has demonstrated a lower incidence of breast,ovarian and large bowel tumours in populations consuming dietscontaining substantial amounts of isoflavones than in those consumingonly small amounts of these substances.

There is a marked difference in this sense between Asiatic and Westernpopulations.

The prognosis, e.g. of breast tumours, is also better in Asiaticpopulations such as the Japanese than in those of the U.S. or GreatBritain.

In-vitro studies, moreover, have confirmed the antiproliferativeactivity of phyto-oestrogens, as assessed in breast tumour cell lines.

In the case of osteoporosis, too, it has been found that the incidenceof this disease increases in relation to an oestrogen deficiency and islower in Asiatic populations with a diet rich in isoflavonoids than inWestern populations.

It has recently been postulated that phyto-oestrogens may behavedifferently, at oestrogen receptor level, according to the differenttissues, as is the case with the synthetic oestrogens such as tamoxifenor 4-hydroxytamoxifen which act as antagonists at the level of theoestrogen receptors of breast tissue and as partial agonists at thelevel of the vessels and bone tissue.

As regards genistein (4′,5,7-trihydroxyisoflavone), we should alsoconsider other mechanisms of action such as inhibition of membraneATPase and inhibition of tyrosine kinase and topoisomerase II.

It has also been reported that genistein exerts a direct metaboliceffect on bone metabolism and that it is capable of inhibiting bonereuptake in in-vitro cultures of femoral metaphyseal tissue. Genisteinalso protects the endothelial cells against atherogenic risk andprevents or inhibits tumour development. The tumour risk, however,generally appears to be reduced not only by intake of genistein but alsoby soy extracts.

Among the various isoflavones, genistein and daidzin appear to be theones that show the closest interaction with oestrogen receptors.

These properties make phyto-oestrogens valid candidates as substitutesfor oestradiol, presenting none of the latter's side effects and provingsuitable for practically unlimited ingestion, as occurs in thosepopulations whose diets include substantial consumption of vegetablesand legumes.

The metabolic actions of the carnitines are very well known.L-carnitine, acetyl L-carnitine, propionyl L-carnitine and isovalerylL-carnitine all present practically the same activity at themitochondrial level and at the level of β-oxidation of fatty acids,though with some differences according to their kinetics and the tissuesconsidered.

The carnitines also exert a substantial antioxidant action, therebyproviding a protective effect against lipoperoxidation of thephospholipid membrane and against oxidative stress induced at myocardialand endothelial cell level.

The carnitines have also proved to be active on carbohydrate metabolism.In the course of ageing, tissue carnitine concentrations diminish andtherefore so do the metabolic possibilities of the various tissues.Particularly adversely affected are tissues such as bone tissue whichrequire a continuous reconstructive and metabolic functional capabilityon the part of the osteoblasts for maintenance of bone mass.

Surprisingly, it has now been found that a combination compositioncomprising as characterising ingredients:

(a) propionyl L-carnitine or one of its pharmacologically acceptablesalts; and

(b) 4′,5,7-trihydroxyisoflavone (genistein)

is extremely effective in the prevention and/or therapeutic treatment ofosteoporosis and postmenopause syndrome as a result of the potentsynergistic action exerted by its ingredients.

It has also been found that, advantageously, ingredient (a) may furthercomprise a “carnitine” selected from the group consisting ofL-carnitine, acetyl L-carnitine, valeryl L-carnitine, isovalerylL-carnitine or their pharmacologically acceptable salts or mixtures andthat ingredient (b) may further comprise an isoflavone selected from thegroup consisting of 4′,7-dihyrdoxyisoflavone (daidzein), its 7-glycoside(daidzin) and its 4,7-diglycoside or mixture of thereof.

The (a):(b) weight-to-weight ratio ranges from 0.01 to 1:1. In thecomposition, ingredient (b) can be present in the form of an extract ofvegetable products containing it, such as, for example, soybean seeds orlinseed.

Described here below are a number of tests demonstrating the lowtoxicity and good tolerability of the composition according to theinvention as well as the intense synergistic effect produced by itsingredients.

Toxicological Tests

Both the single-dose and prolonged administration of a carnitine mixture(combination consisting of L-carnitine+acetyl L-carnitine+propionylL-carnitine+isovaleryl L-carnitine with a weight-to weight ratio of 1:1between the various carnitines), or propionyl L-carnitine, or themixture of soy isoflavones, or genistein, given for the purposes ofevaluating both the acute and chronic toxicity of the combinationsaccording to the invention, demonstrated the low toxicity and goodtolerability of the products, whether administered alone or incombination.

With the single-dose regimen, it proved possible to administer, both torats and mice, a dose of 600 mg/kg of carnitine mixture, or 600 mg/kg ofpropionyl L-carnitine alone, or 5 g/kg of a soy extract containing 5%isoflavones, or 15 mg/kg of genistein, or various combinations of theseproducts, without any mortality or evident signs of toxicity occurringin the animals thus treated. Equally well tolerated was the prolongedadministration to rats for thirty days consecutively of 2 g/kg of a soyextract containing 5% isoflavones together with 200 mg/kg of carnitinemixture or with 150 mg/kg of propionyl L-carnitine, as well as 5 mg/kggenistein administered in combination for the same period either withthe carnitine mixture or with propionyl L-carnitine. In these tests,too, at the end of the thirtieth day of treatment, no abnormalities of atoxic nature were found either in the various blood-chemistry testsperformed or in the red and white blood cell counts. The histologicalexamination performed on the main organs also failed to reveal anysignificant abnormalities.

Evaluation of Chances in Osteocalcin Concentration

There is a close correlation between changes in plasma levels ofosteocalcin and bone tissue osteoblast activity, and a reduction inosteocalcin plasma levels is an indicator of increased osteoblastactivity which appears to underlie osteoporosis in elderly subjects orin the postmenopausal period in women. These tests were performed on abatch of mice aged at least 7 months, divided into various groups of 10mice each.

While one group was used as a control group, the other groups wereadministered, with their diet, the carnitine mixture (100 mg/kg)consisting, in these tests, as in the others, of a mixture ofL-carnitine+acetyl L-carnitine+propionyl L-carnitine+isovalerylL-carnitine in a weight-to-weight ratio of 1:1, or propionyl L-carnitine(100 mg/kg), or soy extract containing 5% isoflavone (2 g/kg), orgenistein (5 mg/kg), or various combinations of these ingredients. Thetreatment was administered daily for thirty days or sixty daysconsecutively. The serum osteocalcin assay was performed according tothe method described by Grunhaberg (Grunhaberg et al., Meth. Enzymology,207, 516, 1984) taking blood samples from control and treated animalsfrom the supraorbital region.

As can be seen from the results presented in Table 1, the administrationof the carnitine mixture, or propionyl L-carnitine, or soy extract, orgenistein was capable of increasing the serum osteocalcin concentrationsof the animals thus treated, whereas serum osteocalcin levels tended todecrease with age in the control animals. Surprisingly, however, thehighest increases were observed after combined administration of thecarnitine mixture plus soy extract, as well as after administration ofthe combination of propionyl L-carnitine plus genistein.

The increases in osteocalcin concentrations were even more marked in themice treated for sixty days consecutively, while the control animalstreated for sixty days showed an even more marked age-related reductionin osteocalcin levels.

The results of these tests demonstrate, therefore, that there is aclearly detectable potent synergistic effect between the carnitinesconsidered and the isoflavones, and particularly between propionylL-carnitine and genistein. The synergistic effect of the combinationappears to be unpredictable and unsuspected in view of the effectsobtainable with the single isolated ingredients of the combinationaccording to the invention.

Prostacyclin Synthesis Tests

Prostacyclin (PGI₂) is one of the products formed by the action ofcyclo-oxygenase at the level of a fatty acid such as arachidonic acidand, unlike (PG)E₂ or leukotrienes such as (LT)C₁, it does not possessthe inflammatory, vasculospastic, osteoclastic or thrombotic-typeactivities of the prostaglandins, but rather a very appreciablecytoprotective, vasodilator and osteoblastic activity, and its formationis related to the activity of COX₁ rather than to that of COX₂.

The purpose of these tests was to establish whether the administrationto rats of the carnitine mixture (L-carnitine+acetylL-carnitine+propionyl L-carnitine+isovaleryl L-carnitine in aweight-to-weight ratio of 1:1 to one another), or soy extract, orgenistein, or propionyl L-carnitine, or various combinations of theseproducts might lead to an increase in the production of prostacyclin(PGI2). It has been demonstrated, in fact, that the prostaglandins, andprostacyclin in particular, may regulate the production of insulin-likegrowth factor (IGF-1) and thereby influence chondrocyte metabolism.

As is known, moreover, there is a close correlation between IGF-1 andgrowth hormone, and it has been proved that the latter, amongst itsother positive effects on growth, is capable of playing an importantrole in bone remodelling and in osteoblast activity. Prostaglandins canalso regulate several other hormone effects, including those ofoestrogens.

The method used in these tests was the one described by G. R. Elliot inBrit. J. Nutrition, 64, 497, 1990, measuring the release ofprostaglandins by peritoneal macrophages isolated from a batch of ratsthat were administered either the carnitine mixture, or the soy extract,or propionyl L-carnitine, or genistein, or various combinations of theseproducts with their diet for seven days consecutively. The doses givenwere 400 mg/kg of carnitine mixture, or 400 mg/kg of propionylL-carnitine, or 8 g/kg of soy extract, or 40 mg/kg of genistein, or thesame doses of the various products combined. On day 1 of treatment, allthe animals were treated intraperitoneally with 2 cm³ of solutioncontaining 2 mg of carrageenin. After the last day of treatment,peritoneal macrophages were isolated from the controls and treated ratsso as to obtain a 2×10⁻⁶/cm³ cell suspension.

One cm³ of the macrophage preparation thus prepared was incubated for aperiod of two hours in order to evaluate the basal release or releaseafter 30 minutes after being placed in contact with an ionophore such asA2318. The cells were centrifuged and the supernatant analysed for itsPGI₂ content according to the radioimmunological assay method describedby Zijstra et al. (Zijstra, F. J., Vincent, J. E., J. Chromatography,311, 39, 1984).

As can be seen from the results reported in Table 2, administration ofthe carnitine mixture and of propionyl L-carnitine leads to an increasein PGI₂ synthesis in macrophages from the rats treated, whereas theincrease appears only modest in rats treated with soy extract or withgenistein. The increase in PGI₂ synthesis, however, appears to be ofmajor proportions in rats treated with a combination of carnitines plussoy extract, or with a combination of propionyl L-carnitine plus soyextract or genistein.

The increase in prostacyclin release by macrophages from animals treatedwith these combinations shows a marked potent synergistic effect.

Osteoblastic Cell Growth Tests

In view of the important role played by osteoblasts in regulating growthand in bone remodelling, a series of tests was conducted to evaluatewhether the presence of carnitines or isoflavonoids and genistein couldinfluence the growth of osteoblastic cells in vitro. To this end, mouseosteoblastic cells (MC3T3 osteoblast-like cells), after beingtrypsinated and placed in a medium enriched with heat-inactivated 2%foetal calf serum, were grown on plates (with wells each containing ca.10,000 cells) in the presence or absence of carnitine mixture(combination of L-carnitine+acetyl L-carnitine+propionylL-carnitine+isovaleryl L-carnitine in a weight-to weight ratio of 1:1),or propionyl L-carnitine, or isoflavones, or genistein, which were addedto the culture medium after suitable solubilisation at concentrationsranging from 0.05 mM of carnitine to 0.005 mM of isoflavones orgenistein. After a 72-hour incubation, the number of cells was countedwith a colorimetric method via reduction ofdimethylthiazole-diphenyltetrazole according to the technique describedby Riancho (Riancho, J. A., J. Bone Mineer. Res., 10, 439, 1995). Theresults are shown in Table 3.

As can be seen from the results obtained in these tests, whereas thecarnitine mixture and propionyl L-carnitine have a modest effect on thegrowth of cells incubated with them, neither the isoflavones norgenistein appear to influence the normal growth rate of the cells ascompared with controls.

The combination of isoflavones or genistein with the carnitine mixtureor with propionyl L-carnitine significantly speeds up the growth ofosteoblasts and does so to a much greater extent than is achieved withthe use of carnitines alone.

In these tests, too, then, a substantial, unexpected synergistic effectbetween carnitines and soy extract or genistein is achieved.

TABLE 1 Serum concentrations of osteocalcin in mice treated with 100mg/kg of carnitine mixture (L-carnitine 25 mg + acetyl L-carnitine 25mg + propionyl L-carnitine 25 mg + isovaleryl L-carnitine 25 mg), orwith 100 mg/kg of propionyl L-carnitine, or with 100 mg/kg of soyextract containing 5% isoflavones, or with 100 mg/kg of genistein, orwith various combinations of these products. Osteocalcin (ng/ml)Duration of treatment Treatment 30 days 60 days Controls 120.4 ± 8.6 90.5 ± 7.9 Carnitine mixture 136.2 ± 9.5  109.4 ± 8.7  PropionylL-carnitine 130.7 ± 10.1 98.5 ± 8.1 Soy extract 139.4 ± 11.6 112.7 ±9.4  Genistein 135.9 ± 10.2 100.1 ± 10.2 Carnitine mixture + soy extract295.6 ± 19.8 250.5 ± 20.3 Carnitine mixture + genistein   285 ± 20.1245.9 ± 19.8 Propionyl L-carnitine + genistein   289 ± 20.9 258.1 ± 20.6

TABLE 2 Evaluation of the effect of administration of carnitine mixture,propionyl L-carnitine, soy extract or genistein, or various combinationsof these, on prostacyclin synthesis in rat peritoneal macrophages.Macrophage PGI₂ release values compared with controls Treatment (ng/2 ×10⁻⁶ cells) Controls 0.25 ± 0.03  Carnitine mixture 2.7 ± 0.15 PropionylL-carnitine 3.0 ± 0.22 Soy extract 0.35 ± 0.15  Genistein 0.39 ± 0.27 Carnitine mixture + soy extract 4.7 ± 0.31 Carnitine mixture + genistein4.8 ± 0.51 Propionyl L-carnitine + soy extract 7.2 ± 0.45 PropionylL-carnitine + genistein 6.6 ± 0.55

TABLE 3 Effect of carnitine mixture, propionyl L-carnitine, soy extractor genistein, alone and in various combinations, on MC3T3osteoblast-like cells. Percentage growth values Treatment compared withcontrols Carnitine mixture +15 ± 0.9 Propionyl L-carnitine +18 ± 1.2 Soyextract  −8 ± 0.5 Genistein  +5 ± 1.5 Carnitine mixture + soy extract+26 ± 2.5 Carnitine mixture + genistein +28 ± 3.3 PropionylL-carnitine + soy extract +25 ± 6.0 Propionyl L-carnitine + genistein+31 ± 4.0

Some illustrative, non-limiting examples of formulations according tothe invention, are reported hereinbelow:

1) Carnitine mixture mg 500 (L-carnitine mg 125, acetyl L-carnitine mg125, propionyl L-carnitine mg 125, isovaleryl L-carnitine mg 125) Soyextract (titled 5% in isoflavon) mg 500 2) Carnitine mixture mg 200(L-carnitine mg 50, acetyl L-carnitine mg 50, propionyl L-carnitine mg50, isovaleryl L-carnitine mg 50) Soy extract (titled 5% in isoflavon)mg 200 3) Propionyl L-carnitine mg 500 Soy extract (titled 5% inisoflavon) mg 500 4) Propionyl L-carnitine mg 200 Soy extract (titled 5%in isoflavon) mg 200 5) Carnitine mixture mg 500 (L-carnitine mg 125,acetyl L-carnitine mg 125, propionyl L-carnitine mg 125, isovalerylL-carnitine mg 125) Genistein mg 25 6) Carnitine mixture mg 200(L-carnitine mg 50, acetyl L-carnitine mg 50, propionyl L-carnitine mg50, isovaleryl L-carnitine mg 50) Genistein mg 10 7) PropionylL-carnitine mg 500 Genistein mg 10 8) Propionyl L-carnitine mg 200Genistein mg 10 9) Carnitine mixture mg 200 (L-carnitine mg 50, acetylL-carnitine mg 50, propionyl L-carnitine mg 50, isovaleryl L-carnitinemg 50) Soybean seeds extract (titled 5% in isoflavon) mg 200 Isoflavonicextract of linseeds mg 50 Vit. D mg 5 Calcium mg 50 Vit. E. mg 20 CoQ10mg 10 Chromium mg 5 Zinc mg 5 Magnesium mg 5 Selenium methionine mg 0.1Pyridoxine mg 20 Vit. C mg 50 10) Carnitine mixture mg 250 L-carnitinemg 75, acetyl L-carnitine mg 75, propionyl L-carnitine mg 75, isovalerylL-carnitine mg 75) Soybean seeds extract (titled 5% in isoflavon) mg 250Eicosapentaenoic Acid (EPA) mg 50 Docosahexaenoic Acid (DHA) mg 25Isoflavonic extract of linseeds mg 50 Resveratrol mg 2 Vit. D mg 5Calcium mg 50 Vit. E. mg 10 CoQI0 mg 10 Chromium mg 5 Zinc mg 5Magnesium mg 5 Selenium methionine mg 0.1 Pyridoxine mg 50 Vit. C mg 50

What is meant by pharmacologically acceptable salt of L-carnitine oralkanoyl L-carnitine is any salt of these active ingredients with anacid that does not give rise to unwanted toxic or side effects. Theseacids are well known to pharmacologists and pharmacy experts.

Non-limiting examples of suitable salts are the following: chloride;bromide; iodide; aspartate, acid aspartate; citrate, acid citrate;tartrate; phosphate, acid phosphate; fumarate; acid fumarate;glycerophosphate; glucose phosphate; lactate; maleate, acid maleate;orotate; oxalate, acid oxalate; sulphate, acid sulphate,trichloroacetate, trifluoroacetate and methanesulphonate.

A list of FDA-approved pharmacologically acceptable salts is given inInt. J. of Pharm. 33, (1986), 201-217; this latter publication isincorporated herein by reference.

The composition of the present invention can also comprise vitamins,coenzymes, mineral substances and antioxidants.

Suitable excipients to be used for formulating the compositions, havingregard to the administrattion route of choice, shall be apparent topharmacy and food industry experts.

What is claimed is:
 1. A composition, which comprises: a) propionylL-carnitine or a pharmacologically acceptable salt thereof; and b)4′,5,7-trihydroxyisoflavone, each being present in an amount effectivefor the treatment of osteoporosis or menopause syndrome or both.
 2. Thecomposition of claim 1, wherein ingredient a) further comprises acarnitine comprising L-carnitine, valeryl L-carnitine, isovalerylL-carnitine or the pharmacologically acceptable salts thereof ormixtures thereof.
 3. The composition of claim 1, wherein ingredient b)further comprises an isoflavone comprising 4′,7-dihydroxyisoflavone(daidzein), the 7-glucoside thereof (daidzin), the 4,7-diglucosidethereof or mixtures thereof.
 4. The composition of claim 1, wherein theratio of a):b) is from 1:0.01 to 1:1.
 5. The composition of claim 1,wherein the ingredient b) is in the form of vegetal extracts whichcomprise said ingredient b).
 6. The composition of claim 5, wherein saidvegetal extracts comprise soybean seed or linseed extracts.
 7. Thecomposition of claim 1, wherein the pharmacologically acceptable salt ofL-carnitine or alkanoyl L-carnitine is selected from the groupconsisting of chloride, bromide, iodide, aspartate, acid aspartate,citrate, acid citrate, tartrate, phosphate, acid phosphate, fumarate,acid fumarate, glycerophosphate; glucose phosphate, lactate, maleate,acid maleate, orotate, acid oxalate, sulphate, acid sulphate,trichloroacetate, trifluoroacetate and methane sulfonate.
 8. Thecomposition of claim 1, which further comprises vitamins, coenzymes,mineral substances or antioxidants or a combination thereof.
 9. Thecomposition of claim 1, which is in a form of an orally administrabledietary supplement.
 10. The composition of claim 6, wherein said vegetalextracts comprise soy extract.
 11. The composition of claim 8, whereinsaid vitamins comprise vitamins C, D or E or a mixture thereof.
 12. Thecomposition of claim 8, wherein said mineral substances comprisesubstances containing calcium, chromium, magnesium, or selenium or amixture thereof.
 13. The composition of claim 1, which is in the form ofan orally, parenterally, rectally or transdermally administrablemedicament.
 14. The composition of claim 13, which is in a form ofpills, tablets, capsules, granulates, syrup, vials or drops.
 15. Thedietary supplement of claim 14, which is in a solid form.
 16. Thedietary supplement of claim 14, which is in a semi-solid or liquid form.17. The dietary supplement of claim 14, which is in a form of pills,tablets, capsules, granulates or syrup.
 18. A dietary supplement,comprising: a) the composition of claim 1, and b) a carrier.